DESCRIPTION: In the era of effective antiretroviral therapy, treated HIV-infected adults have a greater risk of non-AIDS related morbidity, which includes cardiovascular disease, neurocognitive disease, osteoporosis, liver disease, kidney disease, and some cancers. Among the factors that contribute to the risk of non-AIDS complications are antiretroviral drug toxicity,a high prevalence of traditional risk factors (such as substance abuse, obesity, and hypertension), and immune dysfunction and inflammation. In fact, illicit drug use remains the second most common mode of exposure to HIV among AIDS cases nationwide, representing 31% of total diagnoses. In addition to drug use as a factor in initial exposure to HIV, ongoing drug use, correlates of the lifestyles associated with drug use, and lack of access and adherence to treatments for drug use and HIV infection are among the related factors that exacerbate disease progression. In particular, the gastrointestinal tract and its resultant loss of barrier function i a major target for acute HIV infection and drugs of abuse, leading to the occurrence of ischemic lesions secondary to inflammation. Thus, negative synergy between HIV infection and drug use impacting intestinal permeability is central to this proposal. Currently the therapeutic focus for the HIV-infected population is on (i) improved antiretroviral compounds, (ii) cure-based strategies directed at the latent viral reservoir, and (iii) anti-inflammatory, probiotic, antibiotc, and anti-coagulation treatments that target systemic immune activation and hypercoagulability. This application outlines an entirely distinct molecular and cellular target for HIV treatment - repairing the intestinal barrier defect. We reason that HIV- and illicit drug-mediated breakdown in the intestinal mucosa leads to chronic exposure to translocated microbial products, which drive systemic inflammation. These subtle elevations in both inflammatory and coagulation biomarkers are associated with dramatic and sustained increases in risk of all-cause morbidity and mortality in HIV. We therefore propose an innovative three-tiered research strategy to alter the conversation in the HIV scientific community, informed by the augmentation in intestinal damage due to the joint insult of HIV infection and use of illicit drugs. (i) We will define in vito the molecular and cellular mechanisms by which mucosal T cell depletion, accompanied by the preferential decrease in IL-17 and IL-22 production, antiretroviral drug toxicity, morphogenetic patterning (by the Wnt, Notch, and hedgehog pathways), enterocyte apoptosis, and lamina propria fibrosis (due to HIV infection) and intestinal ischemic damage (due to drug use) combine to increase intestinal permeability (IP) via a loss in epithelial integrity and homeostasis. (ii) Working in vivo in the SIV primate model, we will test directly the ability of exogenous IL-17 and IL-22 to decrease intestinal permeability, reduce systemic inflammation, and possibly alter the disease course. Finally, (iii) we will test our hypothesis that focusing on epithelial repair is a transformative approach to HIV- and illicit drug-promoted mucosal damage, by initiating a pilot clinical study with human Growth Hormone (hGH) as the therapeutic and a reduction of intestinal permeability, a decline in circulating microbial products, and a decrease in biomarkers of hypercoagulability and inflammation, as the clinical endpoints. We hope to establish a new paradigm in which we expect to identify novel therapeutic strategies to heal the breached epithelium, and subsequently stem the translocation of microbial products, minimize systemic inflammation, and treat the HIV-infected drug user.